Week 8 - Drugs and Receptors Flashcards
How do drugs produce their effects?
By interacting with targets
- These are mainly proteins
What is molarity?
The concentration of drug molecules around receptors
- Critical in determining drug action
- Molarity (M) = (g/L)/Mr
- 1 mole contains 6x10^23 particles
- Drugs of equivalent molar concentration have the same concentration of drug molecules
In terms of moles, how big is picomolar?
10^-12 M
Describe the binding of drugs to receptors
- Usually reversible
- Governed by association and dissociation
- Binding obeys the law of mass action: i.e. it is related to the concentrations of both the reactants and products
What are agonists?
Drugs that bind to receptors and cause a response
- They have both affinity and intrinsic affinity
What are antagonists?
Drugs that bind to receptors but do not cause a response
- They have affinity but no efficacy
- They block the effects of agonists
What dictates drug action?
Affinity and intrinsic efficacy
- Binding is governed by affinity
- Activation is governed by intrinsic efficacy
What is intrinsic efficacy?
The ability to produce an active form of the receptor
What is efficacy?
The ability of an agonist to cause a response in a cell or tissue
- Depends on intrinsic efficacy and cell/tissue-dependent factors
- Measured in relative terms
- – Agonists with different Emax values have different efficacy, but agonists with the same Emax values may not have identical efficacy
What is Kd?
A measure of affinity
- Dissociation constant
- The lower the value, the higher the affinity
- At the Kd concentration, 50% of receptor will be occupied irrespective of the number of receptors
What is EC50?
The effective concentration giving 50% of the maximal response
- A measure of potency
What is potency?
The amount of drug needed to produce an effect
- A combination of both affinity and efficacy
- Also governed by the number of receptors (cell/tissue-dependent factor)
What is IC50?
The inhibitory concentration giving 50% of the maximum inhibition
- For inhibitory drugs
What could a drug response be?
- Change in signalling pathway
- Change in cell or tissue behaviour
Which graphs can you use to measure the response of a drug?
- Concentration-response curves: when measuring a response in cells or tissues
- Dose-response curves: when measuring responses in a whole animal
Which properties are required for a drug?
- Affinity (does it bind?)
- Efficacy (does it do what it is supposed to do?)
- Selectivity (off-target effects?)
- Drug metabolism/pharmacokinetics (how does the body deal with the drug)
- Physicochemical properties (solubility, pH, stbility, crystallinity)
What are spare receptors?
Some tissues have more receptors than required to produce a maximum response
- I.e. They have spare receptors
- They increase sensitivity
What is the effect of changing the number of receptors?
It changes agonist potency
- This can affect the maximal response
When can the number of receptors be changed?
- In response to low activity: upregulation of receptors occurs to increase sensitivity
- In response to high activity: downregulation of receptors occurs in decrease sensitivity
What are partial agonists?
Drugs that cannot produce a maximal effect, even with full receptor occupancy
- EC50 = Kd
- They can be more of less potent than full agonists
- Partial agonism is a property of the drug in a particular system (may be a partial agonist in tissue A, but a full agonist in tissue B)
- They have lower efficacy than full agonists in the same system
What is reversible competitive antagonism?
A type of antagonism
- Depends on dynamic equilibrium between ligands and receptors
- The inhibition is surmountable (overcome) by addition of more agonist
- Commonest
- Causes a parallel shift to the right of the agonist concentration-response curve
What is irreversible competitive antagonism?
A type of antagonism
- Occurs when the antagonist dissociates very slowly or not at all
- The inhibition is non-surmountable
- Causes a parallel shift to the right of the agonist concentration-response curve
- At higher concentrations, it suppresses the maximal response
What is non-competitive antagonism?
A type of antagonism
- Generally a post-receptor or allosteric event
- Binds to the orthosteric site rather than the allosteric site, so molecules can still bind
What is desensitisation?
A loss of functional response
What are the mechanisms of desensitisation?
- Modification of the receptor by phosphorylation (short-term)
- Reversible receptor internalisation
- Down-regulation (long-term)
What is drug tolerance?
A person’s diminished response to a drug
- Occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug
What is supersensitivity?
The adaptive response by a tissue to overcome the effect of a drug treatment
- It may cause the cell to produce more of the receptors that are being blocked
- Has no effect when drug treatment is continued, but will cause a massive response when stopped
What is homologous desensitisation?
Agonist-induced desensitisation of the same receptor that produced it
- I.e. When a receptor decreases its response to a signalling molecule when that agonist is in high concentration
What is heterologous desensitisation?
Unresponsiveness of a cell to a variety of other agonists after prolonged stimulation by 1 agonist
- I.e. desensitises other receptors
- Usually occurs by receptor internalisation
